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Biomedical subjects

P Frost

Publications and source records attributed to P Frost.

At least 55 records · Page 3Linked to original sources
PubMed1997

The route of nutritional support in the critically ill: physiological and economical considerations.

Although it generally is accepted that early enteral nutrition is of benefit to critically ill patients, there is little evidence to support this assertion. Nevertheless, enteral nutrition has many advantages over total parenteral nutrition (TPN), the latter being associated with several complications. Animal studies have shown that injury and infection can lead to gut atrophy and increased mucosal permeability. Translocation of bacteria and endotoxin in these animal models may initiate a systemic inflammatory response and cause multiple organ failure (MOF). Again, there is little direct evidence to suggest that similar mechanisms operate in humans. As a cause of MOF, simple splanchnic ischemia and reperfusion may be sufficient with no absolute requirement for translocation. In this setting, enteral nutrition may preserve splanchnic blood flow and prevent mucosal breakdown. Unfortunately there is a widespread misconception that gastric stasis, the absence of bowel sounds, and recent abdominal surgery preclude enteral feeding. There are few absolute contraindications to early enteral feeding and with motivated staff, the use of prokinetics, and the availability of jejunal feeding tubes, the majority of intensive care patients can be fed enterally. Enteral feeding is more cost effective than TPN, but TPN remains a common therapeutic intervention in the intensive care unit and represents a significant burden on health care budgets. Nutrition support teams have led to savings, particularly by identifying patients who have been inappropriately prescribed TPN and also by preventing excessive enteral feeding.

Animals↗
PubMed1997

Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination.

Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyze the immunogenicity and efficacy of an HIV-1 DNA vaccine encoding env, rev and gag/pol in a chimpanzee model system. The immunized animals developed specific cellular and humoral immune responses. Animals were challenged with a heterologous chimpanzee titered stock of HIV-1 SF2 virus and followed for 48 weeks after challenge. Polymerase chain reaction coupled with reverse transcription (RT-PCR) results indicated infection in the control animal, whereas those animals vaccinated with the DNA constructs were protected from the establishment of infection. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.

AIDS Vaccines↗
PubMed1997

Overcoming misinformation effects in eyewitness memory: effects of encoding time and event cues.

Eyewitness memory is often distorted when misleading information is presented to subjects after encoding. Three experiments explored ways to overcome these misinformation effects. In Experiment 1, subjects viewed slides of a robbery, at a rate of four or seven seconds per slide. Five minutes later subjects were given a recognition test with few (1-3) or numerous (6-13) event cues. Providing numerous retrieval cues improved overall performance, but did not reduce the effects of misinformation. With week-long delays (Experiment 2) numerous retrieval cues did eliminate misinformation effects, but only when subjects viewed slides at the slower rate (seven seconds per slide). Experiment 3 essentially replicated this pattern, using a modified test to eliminate any biasing effects of distractors. Given adequate encoding and numerous retrieval cues, misinformation effects were eliminated, suggesting that under some conditions misinformation makes event memory inaccessible, but not unavailable.

Crime↗
PubMed1997

Chemosensitization of human prostate carcinoma cell lines to anti-fas-mediated cytotoxicity and apoptosis.

Androgen ablation has been an effective treatment in patients with advanced prostate cancer. However, most treated patients develop hormonally resistant disease and do not respond to conventional chemotherapy. Immunotherapy against prostate cancer is an alternative approach in overcoming hormonal/drug-resistant prostate cancer. Cytotoxic immune lymphocytes kill target cells via the perforin/granzyme and the Fas-ligand (Fas-L) pathways. We hypothesize that tumor cells respond poorly to immunotherapy by developing resistance to killing by the Fas-L mechanism. This study investigated whether prostate tumor cells are sensitive to Fas-mediated killing. The human prostate carcinoma cell lines DU145, PC-3, and LnCAP were examined for their sensitivity to killing and apoptosis by the Fas-L agonist anti-Fas antibody and CTLs. All three lines moderately expressed the Fas antigen on the cell surface; however, all three lines were relatively resistant to cytotoxicity mediated by anti-Fas (CH-11) antibody. Pretreatment of DU145 and PC-3 with subtoxic concentrations of drugs followed by anti-Fas antibody resulted in synergistic cytotoxicity and apoptosis, whereas only an additive effect was obtained with LnCAP. Chemosensitization with drugs and anti-Fas was completely blocked by the addition of neutralizing anti-Fas antibody. The murine CTL hybridoma, PMMI, which kills only via the Fas-L pathway, was able to kill chemosensitized PC-3 and DU145 but not LnCAP cells. Furthermore, this cytotoxicity was blocked by anti-Fas neutralizing antibody. Chemosensitization of PC-3 and DU145 prostate tumor cells was not due to up-regulation of Fas-receptor antigen expression. Treatment of tumor cells with cisplatin did not down-regulate the antiapoptotic genes bcl-2, FAP-1, and c-myc. Further, there was no induction by cisplatin of Fas-L on the tumor cells, thus ruling out Fas/Fas-L-mediated autologous killing. These findings demonstrate that pretreatment of drug-resistant/CTL-resistant prostate DU145 and PC-3 tumor cells with subtoxic concentrations of certain chemotherapeutic drugs sensitizes the tumor cells to Fas-mediated cytotoxicity. These findings suggest that chemosensitization of tumor cells should optimize the response to immunotherapeutic interventions in the treatment of hormone-resistant/drug-resistant prostate cancer.

Animals↗
PubMed1996

In vivo protective anti-HIV immune responses in non-human primates through DNA immunization.

An effective immune response involves the specific recognition of and elimination of an infectious organism at multiple levels. In this context DNA immunization can present functional antigenic proteins to the host for recognition by all arms of the immune system, yet provides the opportunity to delete any genes of the infectious organism which code for antigens or pieces of antigens that may have deleterious effects. Our group has developed the use of nucleic acid immunization as a possible method of vaccination against Human immunodeficiency virus type 1 (HIV-1) [1,2,3,10,11,12]. Sera from non-human primates immunized with DNA vectors that express the envelope proteins from HIV-1 contain antibodies specific to the HIV-1 envelope. These sera also neutralize HIV-1 infection in vitro and inhibit cell to cell infection in tissue culture. Analysis of cellular responses is equally encouraging. T cell proliferation as well as cytotoxic T cell lysis of relevant env expressing target cells were observed. In addition, evidence that DNA vaccines are capable of inducing a protective response against live virus was demonstrated using a chimeric SIV/HIV (SHIV) challenge in vaccinated cynomologous macaques. We found that nucleic acid vaccination induced protection from challenge in one out of four immunized cynomolgus macaques and viral load was lower in the vaccinated group of animals versus the control group of animals. These data encouraged us to analyze this vaccination technique in chimpanzees, the most closely related animal species to man. We observed the induction of both cellular and humoral immune responses with a DNA vaccine in chimpanzees. These studies demonstrate the utility of this technology to induce relevant immune responses in primates which may ultimately lead to effective vaccines.

AIDS Vaccines↗
PubMed1996

Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1.

To test whether the protective effects of attenuated simian immunodeficiency virus vaccines in macaques were applicable to the human immunodeficiency virus type 1 (HIV-1)-chimpanzee system, two groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2) were each challenged with a heterologous clade B virus, HIV-1(DH12). Following challenge, the parameters measured included virus isolation (from plasma, peripheral blood mononuclear cells, and lymph node tissue); quantitative DNA PCR using primers capable of distinguishing HIV-1(IIIB), HIV-1(SF2), and HIV-1(DH12) from one another; and serologic assays to monitor changes in binding and neutralizing antibodies. In contrast to an HIV-1-naive chimpanzee that rapidly became infected following the inoculation of HIV-1(DH12), the two chimpanzees previously infected with HIV-1(IIIB) resisted repeated and escalating inoculations of HIV-1(DH12), as monitored by virus isolation and PCR. The two animals previously infected with HIV-1(SF2) became infected with HIV-1(DH12) but in contrast to the case with the HIV-1-naive chimpanzee, no cell-free viral RNA was detected in the plasma by the branched DNA procedure and levels of peripheral blood mononuclear cell-associated viral DNA were reduced 35- to 50-fold.

AIDS Vaccines↗
PubMed1996

Efficacy and Tolerability of Low-dose Simvastatin and Niacin, Alone and in Combination, in Patients With Combined Hyperlipidemia: A Prospective Trial.

BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. METHODS AND RESULTS: In this multicenter, prospective, randomized trial, 180 patients with hypercholesterolemia and hypertriglyceridemia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total, low-density lipoprotein, and very low-density lipoprotein cholesterol and triglycerides by 24%, 29%, 45%, and 31%, respectively, while increasing high-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol-lowering effect of simvastatin; however, the combination was more effective than either monotherapy at raising high-density lipoprotein cholesterol and lowering very low-density lipoprotein cholesterol (P <.05). More patients discontinued treatment because of an adverse event in the niacin (P <.03) and combination groups (P =.06) than the simvastatin group. CONCLUSIONS: Treatment of patients with combined hyperlipidemia and/or low high-density lipoprotein with combination low-dose simvastatin and niacin resulted in large reductions in total, low-density lipoprotein, and very low-density lipoprotein cholesterol and increases in HDL cholesterol. Although the combination was well tolerated in the current trial, its safety needs to be evaluated in larger trials of longer duration.

Journal Article↗
PubMed1995

[Sick leave in relation to occupational environment and family conditions. An analysis of data from a study on health and morbidity performed 86].

Data previously collected by the Danish Institute of Clinical Epidemiology (DICE) in 1986/87 by a structured interview of a sample of the adult Danish population was analysed to evaluate sick leave among 1) persons with preschool children, 2) persons with either physically demanding work or with exposure to chemicals, and 3) persons with mentally demanding employment. Average absence from work in the year previous to the interview was increased in unmarried women with preschool children (9.8 days). Average absence from work increased in a stepwise fashion from 4.7 to 18.7 days with increasing physical work loads, and from 5.6 to 10.1 days with increasing exposure to chemicals. In the group with mentally demanding work, the increased was from 6.3 to 20.0 days up to a load level of five. Risk of long lasting (above 10 days) sick leave was increased among the 52.9% of persons in the study base who either had physically demanding work or who were exposed to chemicals, prevalence rate 1.91 (1.56-2.35, 95% CI), as well as among the 20.9% of persons in the study base with mentally demanding work, prevalence rate 1.68 (1.38-2.05, 95% CI). Logistic regression analysis revealed statistically significant odds ratios also when age, tobacco smoking, marital status, chronic disease and overlap between the risk groups were taken into consideration.

Adult↗
PubMed1995

Mapping of neutralization epitopes on infectious pancreatic necrosis viruses.

We have characterized and mapped variable and conserved neutralization epitopes of serogroup A strains of aquatic birnaviruses. Epitope mapping using monoclonal antibodies (MAbs) and Escherichia coli-expressed deletion fragments of VP2 of the N1 strain of infectious pancreatic necrosis virus (IPNV) demonstrated that two variable epitopes, H8 and B9, depend on the variable region between amino acid 204-330. A conserved neutralization epitope, F2, was shown to depend on the same region as epitopes H8 and B9 but was additionally dependent on amino acids between 153-203. The neutralization epitopes H8, B9 and F2 were also shown to overlap by a competitive binding assay. One conserved neutralization epitope, AS-1, was not exposed on any of the recombinant VP2 deletion fragments and was therefore not possible to map. However, the MAbs AS1 and F2 were partly competitive indicating that these epitopes are overlapping. All neutralization epitopes were independent of a conserved non-neutralization epitope, E4. Our results demonstrate that the central third of VP2 contains several partly overlapping neutralization epitopes, both variable and conserved among serogroup A strains of IPNV.

Antibodies, Monoclonal↗
PubMed1995

Immunotoxicity of cocaethylene.

This report describes the response of normal human T cells to stimulation in vitro in the presence of nano-micromolar concentrations of cocaethylene. Thymidine incorporation by concanavalin A-stimulated peripheral blood mononuclear cells was generally blunted by cocaethylene, albeit to different degrees depending upon the donor tested. The formation of concanavalin A-induced blast cells was decreased by increasing concentrations of cocaethylene. The production of interleukin-2 was also blunted in a dose-dependent fashion by cocaethylene, and this outcome was more consistently observed in stimulated peripheral blood mononuclear cells, compared to unseparated whole blood preparations. An inverse dose dependence was obtained in relation to the response of blast cells to recombinant human interleukin-2 in the presence of cocaethylene. These lines of evidence, taken together with our preliminary studies aimed at testing the effect of cocaethylene on the expression of certain membrane markers of activation (i.e., interleukin-2 receptor, transferrin receptor, serine aminopeptidase IV) and the expression of the proliferating cell nuclear antigen (cyclin PCNA), suggest that cocaethylene modulates relatively early events following T cell stimulation probably related to the interleukin-2 system.

Cells, Cultured↗
PubMed1994

Steroid receptor-mediated modulation of CD4+CD62L+ cell homing. Implications for drug abusers.

Naive human T cells home to peripheral lymph nodes via the leukocyte endothelial cell adhesion molecule-1 (LECAM-1, l-selectin, CD62L, Leu8 antigen) they express. We enriched populations of CD4+CD62L+ cells (attachment of Leu8+ T cells to flasks coated with anti-mouse IgG (AIS); Leu8+ T cells, 82.3% pure (+/- 2.3%), enriched for CD4+ cells by incubation over flasks coated with anti-CD4 antibody--this 3-4-day procedure yields an 88 +/- 1.4% recovery. Cells were treated with dexamethasone in vitro for 24-48 h, and monitored by flow cytometry. We found severe toxicity by this steroid at high concentration (10(-6) M: 35% decrease in CD62L+ T cells, 22% drop specifically in CD4+CD62L+ cells), suggesting the onset of receptor-mediated apoptotic events. The toxicity was dose dependent (5% and 7% drop in CD62L+ T and CD4+CD62L+ cells, respectively, at 10(-9) M, the concentration found in plasma 10 h following the administration of 1 mg dexamethasone). One mg of dexamethasone given to normal subjects leads to a 15-20% decrease in circulating CD4+CD62L+ cells at 10 h. This tends to be correlated with a drop in the number of glucocorticoid cytosolic receptors. Thus, steroids seem to modulate CD4+CD62L+ cell homing by means of receptor-mediated mechanisms.

Adult↗
PubMed1994

Absence of HTLV-1 related sequences in MS from high prevalence areas in western Norway.

In Western Norway, long-term follow up epidemiological studies have revealed significant increases in the incidence and prevalence rates of multiple sclerosis (MS) in stable populations, indicating the impact of exogenous factors. In this study 183 MS patients and 102 controls from high prevalence areas in Western Norway were investigated for human T-lymphotropic virus type I (HTLV-1) related sequences by polymerase chain reaction. Using primers targeting the gag, pol and env genes in the HTLV-1 provirus genome, no amplification products were detected in the 183 MS patients or 102 controls. The results strongly suggest that neither HTLV-1 nor a closely related retrovirus participate in the aetiology of MS.

Adult↗
PubMed1994

Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.

PURPOSE: To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC). PATIENTS AND METHODS: Nine hundred twenty-seven consecutive patients referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted. RESULTS: The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes. CONCLUSION: This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.

Adenocarcinoma↗
PubMed1994

Preference for darker faces in photographs at different phases of the menstrual cycle: preliminary assessment of evidence for a hormonal relationship.

Six pairs of photographs showing human faces of both sexes were presented to 98 women who had to choose the more pleasing one of each pair. Faces within each pair were identical except for a slight difference in complexion. For women not taking oral contraceptives, skin-color preference differed significantly between two groups of subjects classified according to the current phase of their self-reported menstrual cycle: darker male faces were judged more positively by subjects in the phase when the estrogen/progesterone ratio was expected to be high than by those in the phase when this ratio was expected to be low. Female faces evoked no such cyclic response. Users of oral contraceptives showed no cyclic response to either male or female faces. These results suggest a mental mechanism whose inputs are (a) hormonal state, (b) visual identification of the sex of the face being observed, and (c) visual recognition of complexion, and whose output enters into evaluation of male and female faces. Replication with direct measures of hormonal state is recommended.

Adult↗
PubMed1993

Organic micropollutants in Swiss sewage sludge.

Sludges from sixteen municipal and eleven industrial Swiss sewage treatment plants were analysed for adsorbable organic compounds (AOX), chlorinated pesticides, polychlorinated biphenyls and polycyclic aromatic hydrocarbons. Except for the AOX values, which were significantly higher (p < 0.05) in industrial sludges, there was no significant difference between industrial and municipal sludges. The AOX values did not correlate with any of the measured pollutants. The methods employed (capillary GC-MS and GC-electron-capture detection) proved to be suitable for monitoring organic micropollutants in industrial and municipal sewage sludges.

Environmental Monitoring↗
PubMed1993

Conversion of an immunogenic human immunodeficiency virus (HIV) envelope synthetic peptide to a tolerogen in chimpanzees by the fusogenic domain of HIV gp41 envelope protein.

The fusogenic (F) domain of human immunodeficiency virus (HIV) gp41 envelope (env) protein has sequence similarities to many virus and mediates the fusion of HIV-infected cells. During a survey of the immunogenicity of HIV env peptides in chimpanzees, we have observed that HIV peptide immunogenicity was dramatically altered by the NH2-terminal synthesis of the gp41 F domain to an otherwise immunogenic peptide. We compared two hybrid peptide types comprised of T helper (Th) and B cell epitopes of HIV gp120 env protein for their immunogenicity in chimpanzees. The Th-B epitope hybrid peptides contained the HIV gp120 Th cell determinant, T1 (amino acids [aa] 428-440)-synthesized NH2 terminal to gp120 V3 loop peptides, which contain B cell epitopes that induce anti-HIV-neutralizing antibodies (SP10IIIB [aa 303-321] and SP10IIIB [A] [aa 303-327]). The F-Th-B peptide contained the HIV gp41 F domain of HIVIIIB gp41 (aa 519-530)-synthesized NH2 terminal to the Th-B peptide. Whereas Th-B peptides were potent immunogens for chimpanzee antibody and T cell-proliferative responses, the F-Th-B peptide induced lower anti-HIV gp120 T and B cell responses. Moreover, immunization of chimpanzees with F-Th-B peptide but not Th-B peptides induced a significant decrease in peripheral blood T lymphocytes (mean decrease during immunization, 52%; p < 0.02). Chimpanzees previously immunized with F-Th-B peptide did not respond well to immunization with Th-B peptide with T or B cell responses to HIV peptides, demonstrating that the F-Th-B peptide induced immune hyporesponsiveness to Th and B HIV gp120 env determinants. These observations raise the hypothesis that the HIV gp41 env F domain may be a biologically active immunoregulatory peptide in vivo, and by an as yet uncharacterized mechanism, promotes primate immune system hyporesponsiveness to otherwise immunogenic peptides.

Amino Acid Sequence↗